期刊
AIDS RESEARCH AND HUMAN RETROVIRUSES
卷 33, 期 7, 页码 690-702出版社
MARY ANN LIEBERT, INC
DOI: 10.1089/aid.2016.0273
关键词
HIV; macrophages; priming; transcriptome; STAT
资金
- National Institute on Drug Abuse [R01 DA031017]
- National Institute of Allergy and Infectious Diseases [K22 AI095015, R56 AI108434]
- Laura McClamma Endowment
- Stephany W. Holloway University Chair for HIV/AIDS Research
- Center for Research in Pediatric Immune Deficiency
Macrophages play important roles in HIV-1 pathogenesis as targets for viral replication and mediators of chronic inflammation. Similar to IFN-priming, HIV-1 primes macrophages, resulting in hyperresponsiveness to subsequent toll-like receptor (TLR) stimulation and increased inflammatory cytokine production. However, the specific molecular mechanism of HIV-1 priming and whether cells must be productively infected or if uninfected bystander cells also are primed by HIV-1 remains unclear. To explore these questions, human macrophages were primed by IFN or infected with HIV-1 before activation by TLR ligands. Transcriptome profiling by microarray revealed a gene expression profile for IFN-primed cells that was further modulated by the addition of lipopolysaccharide (LPS). HIV-1 infection elicited a gene expression profile that correlated strongly with the profile induced by IFN (r=.679, p=.003). Similar to IFN, HIV-1 enhanced TLR ligand-induced tumor necrosis factor (TNF) protein expression and release. Increased TNF production was limited to productively infected cells. Specific signal transducer and activator of transcription (STAT)1 and STAT3 inhibitors suppressed HIV-1-mediated enhancement of TLR-induced TNF expression as well as HIV-1 replication. These findings indicate that viral replication and inflammation are linked through a common IFN-like, STAT-dependent pathway and that HIV-1-induced STAT1 and STAT3 signaling are involved in both inflammation and HIV-1 replication. Systemic innate immune activation is a hallmark of active HIV-1 replication. Our study shows that inflammation may develop as a consequence of HIV-1 triggering STAT-IFN pathways to support viral replication.
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